A great deal of medical investigation has been directed to the elucidation of the role of the endocrine system in the growth of human hair. As the result of such investigations, it is generally agreed that the fine, lightcolored vellus hair, which covers most of the body during childhood, comes under the influence of growth hormone and of androgens to eventually become the coarser and darker terminal hairs which characterize many areas of the adult body.
In each body area, the character of the final hair growth is determined not only by the level of circulating androgen and the sensitivity of the follicles in that area to androgen, but also to the length of time over which the follicles have been exposed. Both pubic and axillary hair appear early in puberty but decrease with the onset of the androgen deficiency of old age. Beard growth and balding, on the other hand, develop late in puberty and outlast the natural diminution of androgen. The desired to discover methods for controlling androgen-dependent conditions has generated a large number of studies dealing with androgen metabolism in skin.
As a result of these studies, it is thought that all steroids, including testosterone, the principal androgen circulating in the plasma in men, enter target tissues by passive diffusion. In some tissues, such as muscle, testosterone binds directly to a cytoplasmic receptor protein permitting translocation of the hormone into the cell nucleus. Once inside, the testosterone-receptor complex brings about synthesis of new proteins necessary for expression of virilizing activities by the cell.
In other tissues, such as skin, intracellular testosterone is first reduced by the enzyme steroid 5-alpha-reductase to the compound dihydrotestosterone before association with the receptor and subsequent nuclear translocation takes place. Thus, in the treatment of androgen-mediated conditions in skin, it is possible to reduce the amount of androgen capable of entering the nucleus by two means.
Firstly, the conversion of serum testosterone to dihydrotestosterone can be prevented by the inhibition of the enzyme steroid 5-alpha-reductase. Secondly, certain compounds can compete with the testosterone or dihydrotestosterone for the cytoplasmic receptor sites. Our invention is the first to demonstrate altering the rate and character of beard hair growth by topical application of antiandrogens (5-alpha-reductase inhibitors and/or cytoplasmic receptor binding agents) in adult males. The action of such antiandrogen compounds in skin can also affect the output of sebaceous glands and the course of male pattern hair growth in females, thus leading to their application in the treatment of acne and female hirsutism. The ideal anti-androgenic agent for purposes of altering beard hair growth is one which is active topically with no significant side effects. Although several topically active antiandrogens have been reported in the art, none claim or teach an effect on the rate and character of male beard hair growth.
U.S. Pat. No. 4,039,669 describes the topical use of 17-alpha-R-androst-4-en-17-beta-ol-3-one or esters thereof where the R is n-propyl or n-butyl for the control of dermatological conditions associated with androgen-mediated conditions such as acne.
U.S. Pat. Nos. 4,139,638 and 4,161,540 describe the use of certain 4'-substituted and 3',4'-disubstituted anilides for the treatment of androgen-dependent disease states such as female hirsutism and acne.
U.S. Pat. No. 4,191,775 discloses that certain 3,4-disubstituted branched-chain fluorinated acylanilides may be used in the topical treatment of androgen-dependent disease conditions such as acne, female hirsutism, and seborrhoea.
U.S. Pat. No. 4,344,941, describes the topical use of certain androgenic 17-alpha-substituted steroids exemplified by 17-beta-hydroxy-1-alpha-methyl-17-alpha-(1-methyl-2-propenyl)-5-alpha-andr ostan-3-one for the treatment of diseases such as acne, seborrhoea, alopecia and female hirsutism.
U.S. Pat. No. 4,367,227 describes a cosmetic composition for reducing sebum secretion from the skin comprising alcoholic solutions of cyproterone acetate.
West German OLS 2,840,144 describes the use of combination of progesterone with either cyproterone acetate or chlormadinone acetate in the topical treatment of androgeninduced hormonal disturbances such as alopecia, female hirsutism, and acne.
Japanese Kokai 58-57308 describes the restoration of hair to bald heads by the topical applications of oxidizing substances such as stabilized chlorine dioxide, potassium bromate, or ozone to supress the enzymatic activity of the reductive enzyme 5-alpha-reductase.
The patent art discloses a number of ways of reducing the growth of human hair as opposed to its conventional removal by cutting, shaving, or depilation. One such method is described in U.S. Pat. No. 3,426,137, which pertains to a process for inhibiting the growth of hair by the topical application to a depilated skin area of a composition containing a substituted benzophenone such as 2-amino-5-chloro-benzophenone. Examples in the patent illustrate the reduction of hair growth on the back area of rabbits and on the arm of a male human subject.
Another process for extending the duration of depilation is described in U.S. Pat. No. 4,370,315. The process therein comprises the topical application of a composition containing a lipoxygenase along with linoleic acid or derivative thereof. The patent describes the application of such composition to various body parts of female human subjects in the majority of which regrowth of hair was clearly perceptible only after six or more weeks.
In U.S. Pat. No. 4,439,432 topical compositions containing progesterone are reported for use in treatment of progesterone deficiency and related conditions, including abnormal hair growth resulting from androgen excess. Further insights on this point may be obtained from the related literature, among which mention may be made of Simpson et al. "The Effect of Topically Applied Progesterone on Sebum Excretion Rate," Br. J. Derm., 100, p. 687 (1979), in which progesterone was reported effective in reducing sebum excretion rates in females, but without effect in males. In Goos et al, "An Improved Method for Evaluating Antiandrogens," Arch. Dermatol. Res., 273, pp. 333-341 (1982), the effect of progesterone on inhibition of hair growth in intact males is doubtful (p. 340, Table 3, Group VI vs. Group X). In Burdick et al, "The Topical Effect of the Antiandrogen Chlormadinone Acetate and Some of Its Chemical Modifications on the Hamster Costovertebral Organ," Br. J. Derm., 82, Supplement 6, p. 19 (1970), antiandrogens were either ineffective or of questionable effect in inhibiting flank organ function in normal intact male hamsters. Similarly, in Girard et al, "Inhibition of Testosterone Metabolism and Lipogenesis in Animal Sebaceous Glands by Progesterone," Arch. Dermatol. Res., 269, pp. 281-290 (1980), progesterone is found effective in the female but not in the male. In all of the above experiments topical antiandrogens were ineffective in males in inhibiting androgenic function. When the female and male responses were compared in both humans and hamsters, only females responded to topical treatment.
In U.S. Pat. No. 4,269,831 a substantial reduction in hair growth of the hamster flank organ is among the effects reported from topical application of 17.beta.-hydroxy-17.alpha.-propylandrost-4-en-3-one. However reduction in the size of the flank organ is also described, leaving a smaller field on which the hair can grow. Therefore, the reduction in hair growth may be a consequence of a decrease in area of the flank organ rather than an alteration in the character of the hair.